The present invention relates generally to reductive methods useful in chemical synthesis. In particular, the present invention provides enantioselective reductive methods using chiral organostannanes and Lewis acids.
The scientific literature contains numerous reports of free-radical reactions proceeding with distereocontrol (see for example, reviews such as Curran et al., Stereochemistry of Radical Reactions, VCH, Weinheim, 1995; Smadja et al., Synlett., 1, 1994; Porter et al., Acc. Chem. Res., 24:296, 1991; and Sibi et al., Acc. Chem. Res., 32:163, 1999). However, there are relatively very few examples of free-radical reactions which proceed with genuine enantiocontrol. The majority of the examples that demonstrate enantioselective outcomes involve the use of chiral auxiliaries and, as a result, are actually further examples of diastereo-selectivity in free-radical chemistry.
Of the remaining few reports, the introduction of asymmetry in the substrate has been achieved through the use of chiral Lewis acid mediation (see, for example, Guindon et al., Tetrahedron Lett., 31:2845, 1990; Guindon et al., J. Am. Chem. Soc., 113:9701, 1991; and Renaud et al., Angew. Chem. Int. Ed., 37:2563, 1998), or by a chiral reagent through the use of chiral ligands on the tin atoms in suitably constructed stannanes (Schumann et al., J. Organomet. Chem., 265:145, 1984; Curran et al., Tetrahedron. Asymmetry, 7:2417, 1996; Blumstein et al., Angew. Chem. Int. Ed., 36:235, 1997; and Schartzkopfetal., Eur. J. Chem., 177, 1998).
It has now been found that the enantioselectivity of free radical reductions using chiral non-racemic stannanes can be enhanced by the use of an appropriate Lewis Acid.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word xe2x80x9ccomprisexe2x80x9d, and variations such as xe2x80x9ccomprisesxe2x80x9d and xe2x80x9ccomprising,xe2x80x9d will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Improved methods for the enantioselective reduction of prochiral carbon radicals using chiral and achiral Lewis acids in conjunction with chiral non-racemic stannanes have now been developed which result in an enhanced enantioselectivity when compared to the use of the chiral non-racemic stannane alone.
Accordingly, the present invention provides a method for enantioselectively reducing a prochiral carbon centred radical having one or more electron donator groups attached directly to the central prochiral carbon atom of the radical, and/or attached to a carbon atom within 1 to 4 atoms of the central prochiral carbon atom, comprising treating said radical with a chiral non-racemic organotin hydride in the presence of a Lewis acid.
Preferably, the electron donator group is attached directly to the central prochiral carbon atom or to a carbon atom within 1 or 2 atoms of the central prochiral carbon atom.
In a particular embodiment, the invention is directed towards a method of producing optically enhanced xcex1 or xcex2-amino acids, by treatment of a prochiral amino acid carbon centred radical with a chiral non-racemic organotin hydride in the presence of a Lewis acid, wherein the central prochiral carbon atom is an xcex1-carbon atom of an xcex1-amino acid.or a xcex2-carbon atom of a xcex2-amino acid.
As used herein, the term xe2x80x9cprochiral carbon centred radicalxe2x80x9d is a radical of formula R1R2R3C., wherein each R residue is different and is not hydrogen. Accordingly, the central prochiral carbon atom is the carbon atom to which the R residues are attached. Reduction of the prochiral carbon centred radical with a hydrogen atom donor affords the chiral compound R1R2R3CH. The present invention thus relates to the preparation of enantioselectively enhanced chiral compounds.
The prochiral carbon centred radical can be generated from any suitable radical precursor using methods known in the art. Exemplary radical precursors include aryl, e.g., phenyl, selenides; aryl, e.g., phenyl, sulfides; aryl, e.g., phenyl, tellurides; xanthates; thionoformates and Barton esters (see, for example, Giese, Radicals in Organic Synthesisxe2x80x94Formation of Cxe2x80x94C Bonds, Pergamon Press, Oxford, 1986, the contents of which are incorporated herein by reference). Particularly suitable radical precursors for generating the prochiral carbon centred radicals for use in the invention are tertiary chiral halosubstrates, i.e., R1R2R3C-halogen, where R1-R3 are different and not hydrogen and halogen is chlorine, bromine or iodine, preferably bromine.
The prochiral carbon centred radicals which can be reduced by the methods of the invention include radicals which bear one or more electron donator groups directly on the prochiral central carbon atom and/or attached to a carbon atom or to the centralprochiral carbon atom, i.e., within 1, 2, 3 or 4 atoms, preferably within 1 or 2 atoms. Suitable electron donator groups include those containing an electron donator atom such as oxygen, nitrogen, and/or sulfur and which will not be affected by the organotin hydride. One example of an electron donator group is a carbonyl group C(xe2x95x90O), present, as, for example, in aldehydes, ketones, carboxy acid, carboxy esters, carboxy amides, anhydrides, lactones, lactams, carbonates, carbamates and thioesters, etc. Other electron donator groups include, thioalkyl groups, amines (unsubstituted or substituted once or twice by, for example, a group selected from alkyl, acyl and aryl), hydroxy groups and ethers (e.g., alkyl and aryl). A preferred electron donator is a carbonyl group. Preferably the carbonyl group is adjacent to, i.e.,xe2x80x94to the chiral carbon to be reduced. Expressed in another way, the prochiral carbon centred radical has at least one electron donator atom within 5 atoms (i.e., 1, 2, 3, 4, or 5) of the central prochiral carbon atom. It will be recognized that some electron donator groups may contain one or more electron donating atoms, e.g., carboxy acid, carboxy ester, thioester, carboxy amide. A prochiral carbon centred radical may also contain more than one electron donating group attached to the central prochiral atom.
Exemplary prochiral carbon centred radicals include those of the formula R1R2R3C., wherein R1-R3 are different (and not hydrogen) and are independently selected from alkyl, alkenyl, alkynyl, aryl, heterocyclyl, acyl, amino, substituted amino, carboxy, anhydride, carboxy ester, carboxy amide, lactone, lactam, thioester, formyl, optionally protected hydroxy, thioalkyl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heterocyclyloxy; or alternatively, any two of R1-R3 can together, with the central prochiral carbon atom, form a mono- or poly-cyclic group or fused polycyclic group including as cycloalkyl, cycloalkenyl, cycloalkynyl, a lactone, a lactam, cyclic anhydride, or heterocyclyl and bi-, tri- and tetracyclic fused combinations thererof. At least one of R1-R3, or a cyclic group formed by any two of R1-R3, contains an electron donator atom within 1 to 5 atoms of the prochiral central carbon atom to be reduced. It will be understood that a radical precursor may contain more than one prochiral radical precursor sites and that reduction may therefore occur at one or more of these sites.
In one preferred embodiment, at least one of R1-R3 is an optionally substituted aryl or heteroaryl group. In another preferred embodiment at least one of R1-R3 is an optionally substituted alkyl, alkenyl, or alkynyl group. In another embodiment, at least one of R1-R3 is a ketone, aldehyde, carboxy acid, carboxy ester, carboxy amide, anhydride, lactone, lactam or thioester, or two of R1-R3 together with the central prochiral carbon atom form a cyclic anhydride, lactam or lactone.
Preferred xe2x80x9cketonesxe2x80x9d have the formula xe2x80x94C(O)xe2x80x94R wherein R can be any residue, having a carbon atom covalently bonded to the carbonyl group, such as alkyl, alkenyl, alkynyl and aryl. An R group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.
Preferred xe2x80x9ccarboxy estersxe2x80x9d have the formula xe2x80x94CO2R wherein R can be any residue, having a carbon atom covalently bonded to the non-carbonyl oxygen atom, for example, alkyl, alkenyl, alkynyl or aryl. An R group may have one or more carbon atoms optionally replaced with one or more heteroatoms, such that R is, for example, heterocyclyl.
Preferred xe2x80x9ccarboxy amidesxe2x80x9d have the formula CO2NRRxe2x80x2 wherein R and Rxe2x80x2 are independently selected from hydrogen and any residue having a carbon atom covalently bonded to the nitrogen atom such as alkyl, alkenyl, alkynyl or aryl. An R or Rxe2x80x2 group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.
Preferred xe2x80x9cthioestersxe2x80x9d have the formula xe2x80x94C(O)SR wherein R can be any residue having a carbon atom covalently bonded to the sulfur atom, such as alkyl, alkenyl, alkynyl or aryl. An R group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl.
Preferred anhydrides contain the moiety xe2x80x94C(O)xe2x80x94OC(O)xe2x80x94 and may be cyclic or acyclic. Preferred acyclic anhydrides contain the moiety xe2x80x94C(O)xe2x80x94Oxe2x80x94C(O)xe2x80x94R wherein R can be any residue, such as alkyl, alkenyl, alkynyl or aryl. An R group may have one or more carbon atoms optionally replaced with one or more heteroatoms to form, for example, heterocyclyl. Preferred cyclic anhydrides contain the moiety xe2x80x94C(O)xe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94 wherein n is 1, e.g., 1, 2, 3, 4, 5 or 6.
Lactones are cyclic residues containing the moiety xe2x80x94C(O)Oxe2x80x94. Preferred lactones have the formula xe2x80x94C(O)Oxe2x80x94Rxe2x80x94 wherein xe2x80x94Rxe2x80x94 can be any residue, having a carbon atom covalently bonded to the non-carbonyl oxygen atom, e.g., alkylene, alkenylene, alkynylene. An R group may have one or more carbon atoms optionally replaced by one or more heteroatoms. Preferred lactones contain the moiety xe2x80x94C(O)xe2x80x94Oxe2x80x94(CH2)nxe2x80x94 wherein n is 2, e.g., 2, 3, 4, 5 or 6.
Lactams are cyclic residues containing the moiety xe2x80x94C(O)xe2x80x94N(Rxe2x80x2)xe2x80x94Rxe2x80x94 wherein Rxe2x80x2 can be hydrogen or any hydrocarbon residue such as alkyl, acyl, aryl or alkenyl. xe2x80x94Rxe2x80x94 can be any hydrocarbon residue having a carbon atom covalently bonded to the nitrogen atom such as alkylene, alkenylene or alkynylene. An Rxe2x80x2 or R group may have one or more carbon atoms optionally replaced by one or more heteroatoms. Preferred lactams contain the moiety xe2x80x94C(O)xe2x80x94N(Rxe2x80x2)xe2x80x94(CH2)nxe2x80x94 wherein n is 2, eg., 2, 3, 4, 5 or 6.
As used herein, the term xe2x80x9calkyxe2x80x9d, denotes straight chain, branched or cyclic hydrocarbon residues, preferably C1-20 alkyl, e.g., C1-10 or C1-6. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methoxyhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethyl-pentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1-methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyl-octyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2-, or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-ethylnonyl, 1-, 2-, 3-, 4- or 5-propylocytl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2-pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Where an alkyl group is referred to generally as xe2x80x9cpropylxe2x80x9d, xe2x80x9cbutylxe2x80x9d etc, it will be understood that this can refer to any of straight, branched and cyclic isomers. An alkyl group may be optionally substituted by one or more optional substituents as herein defined. Accordingly, xe2x80x9calkylxe2x80x9d as used herein is taken to refer to optionally substituted alkyl. Cyclic alkyl may refer to monocyclic alkyl or, polycyclic fused or non-fused carbocyclic groups.
The term xe2x80x9calkenylxe2x80x9d as used herein denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C1-20 alkenyl (e.g., C1-10 or C1-6). Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3-decenyl, 1,3-butadienyl, 1-4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. An alkenyl group may be optionally substituted by one or more optional substitutents as herein defined. Accordingly, xe2x80x9calkenylxe2x80x9d as used herein is taken to refer to optionally substituted alkenyl. Cyclic alkenyl may refer to monocyclic alkenyl or, polycyclic fused or non-fused alkenyl carbocyclic groups.
As used herein the term xe2x80x9calkynylxe2x80x9d denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethynically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined. Unless the number of carbon atoms is specified the term preferably refers to C1-20 alkynyl. Examples include ethynyl, 1-propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers. An alkynyl group may be optionally substituted by one or more optional substitutents as herein defined. Accordingly, xe2x80x9calkynylxe2x80x9d as used herein is taken to refer to optionally substituted alkynyl. Cyclic alkynyl may refer to monocyclic alkynyl or, polycyclic fused or non-fused alkynyl carbocyclic groups.
The terms xe2x80x9calkoxy,xe2x80x9d xe2x80x9calkenoxy,xe2x80x9d xe2x80x9calkenoxy,xe2x80x9d xe2x80x9caryloxyxe2x80x9d and xe2x80x9cheterocyclyloxy,xe2x80x9d respectively, denote alkyl, alkenyl, alkynyl, aril and heterocylclyl groups as hereinbefore defined when linked by oxygen.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, bromine or iodine.
The term xe2x80x9carylxe2x80x9d denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl, chrysenyl. Aryl may be optionally substituted as herein defined and thus xe2x80x9carylxe2x80x9d as used herein is taken to refer to optionally substituted aryl.
The term xe2x80x9cheterocyclicxe2x80x9d denotes mono- or polycarbocyclic groups, which may be fused or conjugated, aromatic (heteroaryl) or non-aromatic, wherein at least one carbon atom is replaced by a heteroatom, preferably selected from nitrogen, sulphur and oxygen. Suitable heterocyclic groups include N-containing heterocyclic groups, such as: (1) unsaturated 3 to 6 membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl or tetrazolyl; (2) saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as, pyrrolidinyl, imidazolidinyl, piperidyl, pyrazolidinyl or piperazinyl; (3) condensed saturated or unsaturated heterocyclic groups containing 1 to 5 nitrogen atoms, such as, indolyl, isoindolyl, indolinyl, isoindolinyl, indolizinyl, isoindolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, purinyl, quinazolinyl, quinoxalinyl, phenanthradinyl, phenathrolinyl, phthalazinyl, naphthyridinyl, cinnolinyl, pteridinyl, perimidinyl or tetrazolopyridazinyl; (4) saturated 3 to 6-membered heteromonocyclic groups containing 1 to 3 oxygen atoms, such as tetrahydrofuranyl, tetrahydropyranyl, tetrahydrodioxinyl; (5) unsaturated 3 to 6-membered hetermonocyclic group containing an oxygen atom, such as, pyranyl, dioxinyl or furyl; (6) condensed saturated or unsaturated heterocyclic groups containing 1 to 3 oxygen atoms, such as benzofuranyl, chromenyl or xanthenyl; (7) unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms, such as, thienyl or dithiolyl; (8) unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, oxazolyl, oxazolinyl, isoxazolyl, furazanyl or oxadiazolyl; (9) saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, morpholinyl; (10) unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as, benzoxazolyl or benzoxadiazolyl; (11) unsaturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolyl, thiazolinyl or thiadiazoyl; (12) saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, thiazolidinyl, thiomorphinyl; and (13) unsaturated condensed heterocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms, such as, benzothiazolyl or benzothiadiazolyl. A heterocyclic group may be optionally substituted by an optional substituent as described herein.
The term xe2x80x9cacylxe2x80x9d denotes a group containing the moiety Cxe2x95x90O (and not being a carboxylic acid, ester or amide or thioester). Preferred acyl includes C(O)xe2x80x94R, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, aryl or heterocyclyl, residue, preferably a C1-20 residue. Examples of acyl include formyl; straight chain or branched alkanoyl such as, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g., naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl); aralkenoyl such as phenylalkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl, e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolyglyoxyloyl and thienylglyoxyloyl. Acyl also refers to optionally substituted acyl.
The term xe2x80x9cacyloxyxe2x80x9d refers to acyl, as herein before defined, when linked by oxygen.
In this specification xe2x80x9coptionally substitutedxe2x80x9d is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, hydroxy, alkoxy, alkenyloxy, aryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, acyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, carboalkoxy, carboaryloxy, alkylthio, arylthio, acylthio, cyano, nitro, sulfate and phosphate groups.
Preferred optional substitutents include alkyl, (e.g., C1-6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (e.g., hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (e.g, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, etc.), alkoxy (e.g., C1-6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halo, trifluoromethyl, trichloromethyl, tribromomethyl. hydroxy, phenyl (which itself may be further substituted), benzyl (wherein benzyl itself may be further substituted), phenoxy (wherein phenyl itself may be further substituted), benzyloxy (wherein benzyl itself may be further substituted), amino, alkylamino (e.g., C1-6alkyl, such as methylamino, ethylamino, propylamino, etc.), dialkylamino (e.g., C1-6 alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (e.g., NHC(O)CH3), phenylamino (wherein phenyl itself may be further substituted), nitro, formyl, xe2x80x94C(O)xe2x80x94alkyl (e.g., C1-6 alkyl, such as acetyl), Oxe2x80x94C(O)xe2x80x94alkyl (e.g., C1-6 alkyl, such as acetyloxy), benzoyl (wherein the phenyl group of the benzoyl may itself be further substituted), carbonyl, (i.e., replacement of CH2 with Cxe2x95x90O) CO2H, CO2alkyl (e.g., C1-6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl ester), CO2 phenyl (wherein phenyl itself may be further substituted), CONH2, CONHphenyl (wherein phenyl itself may be further substituted), CONHbenzyl (wherein benzyl itself may be further substituted), CONHalkyl (e.g., C1-6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl amide), CONHdialkyl (e.g., C1-6 alkyl).
As used herein, xe2x80x9cheteroatomxe2x80x9d refers to any atom other than a carbon atom which may be a ring-member of a cyclic organic compound. Examples of suitable heteroatoms include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, arsenic, sellenium and telluruim.
Exemplary chiral non-racemic organotin hydrides have the formula L1L2L3SnH wherein L1-L3 are ligands, which may be the same or different, and wherein at least one of L1-L3 has a chiral centre. Suitable non-chiral ligands include optionally substituted aryl (e.g., optionally substituted phenyl, and napthyl) and non-chiral alkyl (e.g., butyl). Suitable chiral ligands include menthyl and fused polycyclics such as 3-cholestane and those derived from cholic acid, e.g., 3-24-norcholanyl and 7-24-norcholanyl (Schiesser et al., Phosphorus, Sulfur, Silicon and Related Elements, Vol 150-51, 177, 1999).
Examples of organotin hydrides include (a) (1S,2S,5R)-Menthyldiphenyltin hydride; (b) bis[(1S,2S5R)-menthyl]phenyltin hydride; and (c) 3xcex1-dimethylstannyl-5xcex1-cholestane, which can be prepared in accordance with the procedures described in Daktemieks et al., Organometallics, 3342-3347, 1999. In the following structures, xe2x80x9cmenxe2x80x9d indicates: 
Other suitable organotin hydrides include (d) and (e), shown below, which can be prepared by reaction of the appropriate aryl lithium with bis[(1S,2S,5R)-methyl]phenyltin chloride followed by LiAlH4 reduction (Daktemieks et al., supra, and Jastrzebski et al, J. Organomet. Chem., 1983, 246, C75 and van Koten et al, Tetrahedron 1989, 45, 569). Other aryl tin hydrides can be made in an analogous manner. Further examples of a suitable organotin hydride include (d) as below, where one of the menthyl groups is replaced by a phenyl group (both diasteroisomers). Other exemplary preferred compounds of the invention include, for example, (f) shown below. 
Lewis acids for use with the method of the present invention are compounds which are able to accept an electron pair, ie., co-ordinate with an electron donator. Suitable Lewis acids include transition metal complexes and compounds wherein the metal center can accept an electron pair. Examples of suitable Lewis acids include AlCl3, BF3, BBr3,
BCl3, TiCl4, FeCl3, ZnCl2, zirconocene dichloride (herein after referred to as (i)), trialkylborates (RO3B, wherein each R is an alkyl group which can be the same or different), (S,S)- and (R,R)-(+)-N,Nxe2x80x2-bis(3,5-di-tert-butylsalycidene)-1,2-diaminocyclohexamanganese (III) chloride (hereinafter referred to as (ii) and (iii) respectively) (Jacobson""s catalyst, Jacobsen et al., J. Am. Chem. Soc., 113:7063, 1991). An increase in the size of the Lewis acid may result in an increase in enantioselectivity. (See, for example, entries 3-5, 8-10, 13-15 and 18-20 of Table 1 in Example 1 where the addition of (ii) or (iii) provided greater ee values than the use of (i), with, in many cases, (i) providing a greater enantiomeric excess (ee) compared to BF3.
The reductive methods of the invention are carried out for a time and under conditions sufficient to effect enantioselective reduction of a suitable prochiral radical precursor by hydrogen. Suitable reaction temperatures, solvents and quantities of stannane and initiator for free radical reductions are known in the art (see, for example, Perchyonok et al, Tetrahedron. Lett., 39:5437, 1998 and references cited therein). Preferred solvents include hydrocarbon solvents, e.g., toluene. The reduction is preferably carried out at temperature less than 0xc2x0 C., preferably less than about xe2x88x9230xc2x0 C., more preferably at about xe2x88x9278xc2x0 C. Exemplary initiators include those which are reactive at these temperatures such as AMBM (Tetrahedron Lett., 38:6301, 1997); 9-BBN (Tetrahedron Lett., 39:5437, 1998), 9-alkyl-9-BBN (e.g., alkyl=ethyl, propyl, butyl, etc.).
The stannane is preferably used in an amount of about 0.5-1.5 equivalents of substrate per reductive site, i.e., central prochiral carbon atom, more preferably about 1.1 equivalents, to effect optimum reductive conversion.
The Lewis acid is preferably used in an amount of about 0.9-1.1 equivalents of substrate, per reductive site, i.e., central prochiral carbon atom, more preferably about 1.0 equivalent. Lesser amounts can be used such as 0.1 or 0.5 equivalents although lower enantiomeric excesses (ees) are usually observed. The addition of higher amounts of Lewis acid can also be used, although this does not generally result in an increase in observed ees.
The stereochemistry of the reduced prochiral carbon center in the resulting compound can be R or S.
The methods of the invention may be particularly useful in preparing optically enhanced amino acids. Thus, xcex1- or xcex2-carbon centered radicals derived from xcex1- or xcex2-substituted amino acids may be reduced by the methods of the invention to produce optically enhanced amino acids which may be natural or unnatural, including alanine, asparagine, cysteine, glutamine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, aspartic acid, glutamic acid, arginine, histidine, lysine and their homo derivatives. Other examples include xcex1- and xcex2-straight and branched chain alkyl substituted amino acids, xcex1- and xcex2-cycloalkyl substituted amino acids, and xcex1- and xcex2-aryl substituted amino acids.
The chiral stannanes for the generation of the prochiral carbon centered radical may also be immobilized onto a solid support, e.g., a polymeric support, such as pins, beads or wells, for use in the methods of the invention, e.g., used in combinatorial techniques known in the art.